Solvated ensemble averaging in the calculation of partial atomic charges

In the calculation of partial atomic charges, for use in molecular mechanic s or dynamics simulations, it is common practice to select only a single co nformation for the molecule of interest. For molecules that contain rotatab le bonds, it is preferable to compute the charges from several relevant con formations. We present here results from a charge derivation protocol that determines the partial charges by averaging charges computed for conformati ons selected from explicitly solvated MD simulations, performed under perio dic boundary conditions. This approach leads to partial charges that are we ighted by a realistic population of conformations and that are suitable for condensed phase simulations. This protocol can, in principle, be applied t o any class of molecule and to nonaqueous solvation. Carbohydrates contain numerous hydroxyl groups that exist in an ensemble of orientations in solut ion, and in this report we apply ensemble averaging to a series of methyl g lycosides. We report the extent to which ensemble averaging leads to charge convergence among the various monosaccharides and among the constituent at oms within a given monosaccharide. Due to the large number of conformations (200) in our ensembles, we are able to compute statistically relevant stan dard deviations for the partial charges. An analysis of the standard deviat ions allows us to assess the extent to which equivalent atom types may, nev ertheless, require unique partial charges. The configurations of the hydrox yl groups exert considerable influence on internal energies, and the limits of ensemble averaged charges are discussed in terms of these properties. ( C) 2001 John Wiley & Sons, Inc.